Stroke and cognitive impairment are major causes of death and disability in the US and disproportionately impact blacks. While traditional stroke risk factors such as hypertension and diabetes contribute to racial disparities in cerebrovascular outcomes, they are not sufficient to completely explain these findings, suggesting that non-traditional risk factors play an important role. Disturbances in vitamin D and phosphorus metabolism have emerged as non-traditional risk factors for adverse cardiovascular outcomes. Low 25-hydroxyvitamin D (25D) levels are associated with heart disease and death via broad effects on inflammation, insulin resistance and blood pressure control. Disturbances in phosphorus metabolism stimulate the secretion of fibroblast growth factor 23 (FGF23), a bone-derived hormone that maintains phosphorus homeostasis in part by inhibiting the conversion of 25D to its activated metabolite, 1,25-dihydroxyvitamin D (1,25D). Our group and others showed that higher FGF23 levels were associated with adverse outcomes through direct and indirect effects promoting cardiovascular disease and 1,25D deficiency. Moreover, preliminary data from our group suggest that low vitamin D is an independent risk factor for stroke and cognitive impairment. The primary focus of the current proposal is to build upon this prior work by determining whether low plasma 25D levels and excess plasma FGF23 levels are associated with incident stroke and cognitive impairment in a large, national cohort (Aim 1). In addition, since disorders of vitamin D and phosphorus metabolism are more common and severe in blacks than whites, we will determine if they partly underlie racial disparities in stroke (Aim 2). Finally, given that inflammation, insulin resistance and hypertension are key risk factors for cerebrovascular disease, and are interconnected with disturbances in vitamin D and phosphorus metabolism, we will determine whether they partly mediate the associations of 25D and FGF23 with stroke and cognitive decline. We will test these hypotheses by measuring plasma 25D, FGF23 and other key mediators of mineral metabolism including 1,25D, parathyroid hormone, calcium and phosphate in stored blood samples from a specified case cohort of 2,085 participants of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national prospective study of black and white adults designed to identify novel risk factors for racial disparities in stroke. The case-cohort to be used for this study has available measures of inflammation and insulin resistance, making it uniquely well-suited to test our hypotheses. The results of these studies may have an important impact on the treatment and/or prevention of stroke and cognitive decline. Indeed, 25D deficiency and FGF23 excess are common in the general population, disproportionately impact blacks, and can be treated with safe and relatively inexpensive therapies. Thus, if vitamin D deficiency and excess FGF23 are risk factors for cerebrovascular disease, this would support intervention trials testing the treatment of these disorders in reducing rates of incident stroke and cognitive impairment, particularly among black individuals. PUBLIC HEALTH RELEVANCE: Disorders of vitamin D and phosphorus metabolism are strongly linked to cardiovascular disease. The studies proposed herein will clarify the role of vitamin D deficiency and excess levels of fibroblast growth factor 23 in stroke, cognitive impairment, and racial disparities in these outcomes. Since vitamin D deficiency and elevated fibroblast growth factor 23 levels are common and disproportionately impact blacks, these studies may uncover novel therapeutic strategies for improving cerebrovascular outcomes in the general population, particularly among African Americans.